Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations

Transcription

1 Supplement to January/February 2016 CME ACTIVITY Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations John E. Anderson, MD Jay S. Duker, MD Allen C. Ho, MD John W. Kitchens, MD A CME activity jointly provided by Dannemiller, Retina Today and New Retina MD. Supported by an educational grant from Regeneron and Allergan. Go to medced.com/evolving-issues/?f=okeno to view the archived webinars.

2 Jointly provided by Dannemiller, Retina Today and New Retina MD. Supported by an educational grant from Allergan and Regeneron Pharmaceuticals. Release Date: February 1, 2016 Expiration Date: February 1, 2017 CONTENT SOURCE This continuing medical education (CME) activity is based on content from two webinars held in the fall of INTENDED AUDIENCE This certified CME activity is designed for retina specialists and general ophthalmologists involved in the management of diabetic ocular disease. LEARNING OBJECTIVES Upon completion of this activity, the participant should be able to: Describe the pathophysiology/epidemiology of diabetes Discuss the difference between the microvascular and macrovascular complications of diabetes Explain how these complications affect the ocular system Discuss the latest treatments in diabetic ocular disease STATEMENT OF NEED Diabetes mellitus ( diabetes ) is a growing worldwide epidemic, affecting largely a working age population. By 2035, it is estimated close to 600 million people worldwide will be living with diabetes, a marked increase from the 382 million in Once diagnosed with diabetes, half of the patients are most concerned with ocular complications associated with the systemic disorder. Patients with diabetes are at an increased risk of several morbid and chronic conditions, among them acute coronary syndrome, hypertension, and retinopathy. 2-4 For ophthalmologists, an understanding of the complications of diabetes is crucial to the overall management of the systemic disease and the preservation of vision after diagnosis. Patients with diabetic macular edema (DME) are at an increased risk of developing cardiovascular disease compared to patients with diabetes but without DME. 5 Ophthalmologists are also only one part of the treatment paradigm for patients with diabetes; as previously described these patients tend to have other manifestations of the systemic disorder and treatment is multifactorial. Thus, interpreting the analysis of ocular and systemic VEGF load before and during anti-vegf therapy is more complex than ever. As might be expected, chronic use of the anti-vegf agents in this patient population warrants close monitoring by fluorescein angiography or optical coherence tomography. Both anti-vegf agents ranibizumab and aflibercept were approved for treatment of DME by the FDA in Corticosteroids are also approved for the treatment of DME, 6,7 but bring with them a concern about cataract formation and increased intraocular pressure levels that do not exist with the anti-vegf treatments. 8,9 The diabetic patient population brings with it increased scrutiny of systemic safety when managing the ophthalmic manifestations. Continued understanding of this systemic disorder and how its ocular complications develop is necessary to best serve the patient. 1. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for Diabetes Res Clin Pract. 2014;103(2): Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, Atlanta, GA: US Department of Health and Human Services, Long AN, Dagogo-Jack S. Comorbidities of diabetes and hypertension: mechanisms and approach to target organ protection. J Clin Hypertens (Greenwich). 2011;13(4): Kapur A, De Palma R. Mortality after myocardial infarction in patients with diabetes mellitus. Heart. 2007;93(12): Nguyen-Khoa BA, Goehring EL, Werther W, et al. Hospitalized cardiovascular events in patients with diabetic macular edema. BMC Ophthalmol. 2012;12: Ozurdex [package insert]. Irvine, CA: Allergan Inc., Iluvien [package insert]. Atlanta, GA: Alimera Sciences Inc., Diabetic Retinopathy Clinical Research N. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9): , 9 e1-9. Messenger WB, Beardsley RM, Flaxel CJ. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. Drug Des Devel Ther. 2013;7: ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Dannemiller, Retina Today, and New Retina MD. Dannemiller is accredited by the ACCME to provide continuing medical education for physicians. AMA CREDIT DESIGNATION: Dannemiller designates this print enduring material for a maximum 1.0 AMA PRA Category 1 Credit(s) TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. METHOD OF PARTICIPATION Participants should first read the objectives and other introductory CME/CE information and then proceed to the educational activity. To receive credit for this activity, please visit Credit is provided through February 1, No credit will be given after this date. There is no fee to participate in this activity. In the event you have questions about this activity or are unable to retrieve the certificate, please cme@dannemiller.com and a certificate will be ed within 2 weeks. FACULTY John E. Anderson, MD The Frist Clinic Nashville, Tennessee Jay S. Duker, MD Tufts Medical Center Tufts University School of Medicine Boston, Massachusetts Allen C. Ho, MD Retina Service Wills Eye Institute Philadelphia, Pennsylvania 2 SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016

3 John W. Kitchens, MD Retina Associates of Kentucky Lexington, Kentucky DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Education (ACCME), Dannemiller requires that any person who is in a position to control the content of a CME/CE activity must disclose all financial relationships they have with a commercial interest. John E. Anderson, MD, has had a financial agreement or affiliation during the past year with Astra Zeneca, Abbott Diabetes, Elli Lilly/BI, Janssen, and Sanofi. Jay S. Duker, MD, has had a financial agreement or affiliation during the past year with Alcon/Novartis, Allergan, Carl Zeiss Meditec, CoDa Therapeutics, Eleven Biotherapeutics, EyeNetra, Hemera Biosciences, Lumenis, Ophthotech, OptoVue, Santen, and Thrombogenis. Allen C. Ho, MD, has had a financial agreement or affiliation during the past year with Alcon, Allergan, Beaver-Visotec, Genentech, and Second Sight. John W. Kitchens, MD, has had a financial agreement or affiliation during the past year with Allergan, Bausch + Lomb, Bayer, Carl Zeiss Meditec, and Regeneron. Bernard M. Abrams, MD, content reviewer, and Myra Garcia, Dannemiller project manager, have no financial relationships with commercial interests. The editors at Bryn Mawr Communications LLC have no financial relationships with commercial interests. To resolve identified/potential conflicts of interest, the educational content was fully reviewed by a member of the Dannemiller Clinical Content Review Committee who has nothing to disclose. The resulting certified activity was found to provide educational content that is current, evidence based and commercially balanced. OFF-LABEL STATEMENT Off-label statement provided: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program. DISCLAIMER The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Dannemiller, Retina Today, New Retina MD, Allergan, and Regeneron Pharmaceuticals. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, health care professionals and other individuals should review and consider other publications and materials on the subject. Go to medced.com/evolving-issues/?f=okeno to view the archived webinars. To view the digital version of this print activity, scan the QR code or visit eyetube.net/cme-center and choose the appropriate title. eyetube.net JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 3

4 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations Diabetic eye disease is sweeping the nation, and it falls on retina specialists to treat patients whose diabetes has begun to affect their vision. In the pages that follow, John E. Anderson, MD, will discuss the prevalence of diabetic retinopathy and statistical data of screening results in the United States aimed at detecting diabetic eye disease. Dr. Anderson outlines the screening process and discusses the primary care physician s role in diabetic eye screening. John W. Kitchens, MD, reviews the pathophysiology of diabetic macular edema and proliferative diabetic retinopathy, and also shares a number of treatment options available for patients with these conditions. Cases presented by Allen C. Ho, MD, and Jay S. Duker, MD, illustrate the complexity of diabetic eye disease, and offer a look at how retina specialists can best manage these complicated cases. Current Understandings in DR and DME: Diagnosis and Treatment Objectives There is growing evidence that DME may be a multimodal disease state. By John W. Kitchens, MD Diabetic retinopathy (DR), a microvascular complication of type 1 or 2 diabetes, is the leading cause of blindness among working age adults in the United States. Duration and control of diabetes is the most important risk factor in the development of DR. 1 Chronically elevated blood sugar levels lead to retinal blood vessel (capillary) damage that results in increased permeability and leakage from these vessels. Years of persistently elevated blood glucose levels lead to the development of lack of blood flow and ischemia. The development of new blood vessels (retinal neovascularization) occurs as the body attempts to repair the damage and supply nutritional pathways to the back of the eye. Both the development of diabetic macular edema (DME) and proliferative retinopathy are mediated by a variety of factors, the principle of which is vascular endothelial growth factor (VEGF). DME is a leading cause of moderate vision loss and can cause visual distortion (metamorphopsia), and decreased contrast sensitivity. This can lead to decreased reading ability and inability to drive, among other limitations. DME does not always cause permanent loss of vision, especially if treatment is initiated early in the disease course. 2,3 ME can either be focal or diffuse in pattern, although more typically, DME is classified as either affecting or not affecting the fovea. The mainstays of imaging in patients with DR and DME include optical coherence tomography (OCT), color fundus photography, and fluorescein angiography. DME can be identified most readily on OCT testing. Color fundus photography can document exudates and microaneurysms (Figure 1) as well as the level of diabetic retinopathy present. Areas of leakage, nonperfusion, and occult neovascularization of the retina can be identified using fluorescein angiography (Figures 2 and 3). Figure 1. Fundus photograph of a patient with DME. Exudates and microaneurysms are readily apparent. THERAPY GOALS: DME Although the retinal examination is focused on the impact of the diabetes on ocular structure and function, it should be noted that DR and DME are the consequence of a systemic disease. Therefore, the retinal physician s encounter with a patient to assess diabetic eye disease is an opportunity to educate about the importance of systemic glycemic control and blood pressure monitoring. Often times, ocular imaging gives the patient a first-hand view of how diabetes 4 SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016

5 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations Figure 2. Fluorescein angiogram of the patient in Figure 1. Leakage is seen around the perifoveal area. Figure 3. OCT image of the same eye as in Figures 1 and 2. The area of thickening on the OCT map corresponds to areas of leakage seen on angiography. Bilateral DME Affecting Each Eye Differently By Jay S. Duker, MD Although diabetic macular edema (DME) commonly presents bilaterally, it may have different characteristics and response to therapy in each eye. Thus, an element of individualizing therapy is a need to tailor the management approach to each eye separately. The following case demonstrates that DME can be bilateral with differential response to therapy between each eye. It also demonstrates important learning points with respect to outcomes with laser therapy and suggests how patients should be counseled regarding expected outcomes. CASE INFORMATION A 67-year-old woman with a 15-year history of type 2 diabetes presented for evaluation of DME. Her A1C is 7.8% at the time of the initial evaluation. She has been treated previously with anti-vegf injections in each eye, and panretinal photocoagulation (PRP) on the left eye. She was pseudophakic is both eyes, and presented with visual acuity of 20/20 OD and 20/25 OS. Widefield imaging (Optos) showed clear media and diabetic retinopathy and a fluorescein angiogram showed some diffuse leakage and nonperfusion in the left eye, and in the right eye, previous laser treatment in a PRP fashion and some areas of leakage around the macula (Figure 1). An initial optical coherence tomography (OCT) scan depicted normal contour of the right eye with good central foveal thickness; however, thickening was evident outside of the central fovea. Her left eye had more diffuse DME, central foveal thickness of 341 µm, and there were some cysts present that were visible on the crosssectional OCT (Figure 2). Due to a lack of active disease, and based on no subretinal fluid or intraretinal hard exudates, it was elected to watch the patient at this visit. Figure 1. Baseline widefield imaging demonstrating different disease features in each eye. At a subsequent visit, the area of edema on OCT had increased, supratemporal to fixation on both the right and left eye, but visual acuity remained 20/20 in each eye. Despite the worsening anatomy, because she was asymptomatic and had excellent vision, it was again elected to observe her on this visit. JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 5

6 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations Figure 2. OCT scans showed a relatively healthy right eye but evidence of progression disease in the left. The DME showed progressive worsening upon examination 4 months later (Figure 3). In the right eye, thickening not involving the fovea was present, meaning anti-vegf injections would be off-label in this setting; instead, focal laser treatment was performed in that eye according to ETDRS protocol. In the left eye, the edema waned a little compared with the prior visit, the central foveal thickness was closer to normal, and her visual acuity remained excellent. And so, no treatment was offered for the left eye. At the next visit, there was no change in the status of the right eye and visual acuity remained 20/20. In the left eye, acuity had dropped to 20/40, and the DME now involved the foveal center; as a result, anti-vegf therapy with aflibercept was initiated and continued on a monthly basis. Four months later, the effect of the laser in the right eye became apparent; as well, her left eye responded to anti-vegf therapy with visual acuity at 20/25 (Figure 4). DISCUSSION This case demonstrates that concurrent bilateral DME can affect each eye of a patient differently. The right eye met the criteria for laser treatment according to the ETDRS protocol. There was not an immediate response to laser, although this is not uncommon. The effects of laser therapy may not be apparent until 3 to 6 months after treatment. With this caveat in mind, laser treatment is the only proven therapy for nonfoveal-involving DME. There may also be a place for laser as a rescue therapy in the setting of foveal-involving DME that does not respond to multiple anti-vegf injections. Subthreshold micropulse lasers are now available and may provide good anatomic response with less potential to affect changes to the RPE in the outer retina in the setting of foveal-involving DME. However, it is not clear if there are longterm benefits of subthreshold versus conventional laser. In certain situations, it may be prudent to repeat laser if there is no response after 3 to 6 months, especially if areas of thickening persist outside the fovea. However, when DME involves the fovea, another form of therapy after laser, such as anti-vegfs or corticosteroids, should be considered. Clinical trial data demonstrate a clear benefit of anti-vegf injections compared with immediate or deferred laser for center-involved DME; in the Protocol I study,10 the best visual and anatomic outcomes were with immediate anti-vegf therapy with or without deferred laser. 6 SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016 Figure 3. DME progressed in the right eye requiring laser therapy. It was elected not to treat the left eye during this visit. Figure 4. The left eye ultimately did require anti-vegf therapy as the edema involved the foveal area. Triamcinolone gave similar initial visual acuity results, but, presumably due to the worsening of the cataracts, outcomes were not as positive by 1 year. The presumed benefit of corticosteroid therapy may be different in patients with pseudophakic lens status, although the risk of intraocular pressure changes should be considered. It is interesting to note that this case was treated without the use of angiography after the initial examination. The role of fluorescein angiogram in the management of patients with DME is now controversial. It may be feasible to treat patients on the basis of OCT and the clinical examination and to perform repeat angiography as needed. In the future, it will be interesting to see if the less-invasive OCT angiography changes this paradigm if it is proven to be of equal or greater clinical value. The patient s left eye required a completely different approach to management compared with the right. It is unclear in the published literature what is the threshold for initiating treatment in a case such as this where the diffuse edema worsened while being followed off treatment. Certain benchmarks have been suggested, including at the first sign of abnormal thickening of the foveal center or based on a change in visual symptoms. Because DME in the short-term does not pose a threat to the retina, there is rationale for observation; however, as in this case, visual acuity worsening to 20/40 may be an indication to initiate anti-vegf therapy. Case information courtesy of John W. Kitchens, MD.

7 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations is impacting the eye on a very personal level. Because DME stems from unregulated systemic blood sugar levels, treatment of diabetic complications should complement strategies to encourage proper management of the blood glucose. In fact, clinical trials underscore the utility of controlling blood sugar levels for reducing the progression of retinopathy and reducing the chances of vision loss. In the Diabetes Control and Complications Trial in patients with type 1 diabetes, blood sugar control correlated with a significant reduction in both moderate vision loss and advancing retinopathy. 4 Among individuals with type 2 disease in the United Kingdom Prospective Diabetes Study, 5 the researchers noted a 35% reduced progression per A1C point and a 47% reduction in moderate vision loss associated with good glycemic control. There are a variety of options available for the treatment of vision-threatening DME, including focal laser, intraocular intravitreal steroids, and intraocular anti-vegf agents. The application of the particular treatment modality should consider the individual s circumstances, including the willingness and ability to comply with treatment requirements, as well as disease severity and the patient s control of his or her blood glucose levels. FOCAL LASER THERAPY Focal laser treatment remains the only interventional modality tested and approved for individuals with noncenter-involved DME. In the Early Treatment of Diabetic Retinopathy Study, 6 there was a 50% reduction in 3-line vision loss in the patients who received focal laser treatment with clinically significant DME. However, only 15% of patients improved by 3-lines of vision, and so this modality appears best suited for abating vision loss. In my opinion, there is still a role for laser in treatment of noncenter-involved focal edema, as it is often possible to achieve complete resolution of the edema with no need for continual intravitreal anti-vegf injections (Of note, anti- VEGF use in patients with noncenter-involved DME is an off-label indication, as all of the major anti-vegf trials studied patients with center-involved DME). INTRAOCULAR STEROIDS Laser was the favored treatment for DME following the publication of the ETDRS study in 1985 until the advent of anti-vegf therapy, around In the interim time period, interest arose in the off-label use of intravitreal corticosteroids injections. 7 Although a sometimes effective strategy, intravitreal corticosteroid use can result in intraocular pressure elevation and cataract development. More recently, two sustained release corticosteroid implants have become available and are approved for use by the US Food and Drug Administration (FDA) for the treatment of DME: the dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) and the fluocinolone intravitreal implant (Iluvien, Alimera). These two devices proved remarkably successful in clinical trials, which has caused a rethink in how intravitreal corticosteroids are utilized in DME therapy. The dexamethasone intravitreal implant is a bioerodable implant introduced via a Teflon-coated 23-gauge needle under topical anesthesia that was first approved for edema due to branch retinal vein occlusion and later approved for treatment of uveitis. In the phase 3 MEAD study 8 among patients with center-involved DME, 22% of Figure 4. Anti-VEGF therapy with either prompt or deferred laser outperformed laser alone and steroid plus laser in the DRCR.net Protocol I study. patients in the higher dose group gained 2 or more lines of visual acuity at their final visit after a mean 4 injections over 3 years. Per protocol, patients could only receive a new injection after 6 months; data from the trial indicate the effect began to wane about 4 months after injection, and so a shorter interval between injections may be prudent for most patients. In the study, 59.2% of phakic eyes in the 0.7-mg group required cataract surgery compared to 7.2% of the sham-treated patients, with the majority of cataract surgeries reported in the second and third year of study. Approximately a third of patients treated with an implant required use of glaucoma medication (41.5% in the 0.7 mg group and 37.6% in the 0.35 mg group vs 9.1% in the sham group), but only one patient each in the low- and high-dose groups required incisional surgery (rate=0.6%). Although there is no direct comparison to intravitreal injections, these rates appear favorable compared with historical data on cataract and pressure elevation associated with bolus injections, which follows a differing pharmacokinetic profile: whereas intravitreal injection causes an immediate large spike in the presence of active drug in the vitreous cavity followed by near-zero levels, the implant supplies a smaller spike followed by a sustained, low-level duration of drug. The other implant, the fluocinolone acetonide 0.19-mg intravitreal implant, gained approval in late 2014 based on results of the FAME study. 9 It is a nonbioerodable implant approved for use for up to 36 months. In the FAME trial, nearly 30% of patients with chronic DME gained 3 lines of visual acuity at 3 years, although there were a significant number of reports of cataracts and elevated IOP. In the FAME study, 4.8% of patients required incisional glaucoma surgery. ANTI-VEGF THERAPY The introduction of anti-vegf agents has significantly changed how patients with center-involving DME are managed. As noted previously, laser therapy was the primary mechanism for treating noncenter-involved DME, and it remains a viable option for that indication. For DME in the fovea, however, laser use poses a risk for long-term, vision-threatening changes, and it is therefore less commonly used in this sensitive area of the macula. The first large randomized controlled trial showing that anti-vegf therapy may have the greatest efficacy in DME treatment comes JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 7

8 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations from the DRCR.net Protocol I study, which compared sham and prompt laser, triamcinolone and prompt laser, and ranibizumab (Lucentis, Genentech) with either prompt or deferred laser. 10 Both anti-vegf injection groups outperformed both intravitreal triamcinolone and prompt laser as well as laser alone (Figure 4). These results were sustained over 5 years and patients maintained visual acuity gains with decreasing numbers of injections: patients in the ranibizumab plus deferred laser group received 9, 3, 2, 1, and zero injections per year while maintaining acuity they had gained by year Looking back in the light of data from subsequent pivotal trials, the results of Protocol I offered the first glimpses of information that have shaped how patients are managed on anti-vegf therapy. For instance, there was a suggestion that treatment with anti-vegf DME Treatment in the Real World By Allen C. Ho, MD Phase 3 clinical trials are valuable for establishing the safety and efficacy of the drugs we use in regular clinical practice, but they are rarely directly applicable to the clinical setting. Such is the case with anti-vegf agents used for the treatment of diabetic macular edema (DME), where we can be assured that each of the approved available agents has an established track record due to their involvement in rigorous clinical trials; from ancillary studies, we have reasonable assurance that the off-label medication in this category is at least as safe as the approved agents and likely effective for resolving the anatomy while restoring vision in the majority of cases. However, burdensome treatment demands prescribed by these studies may not be feasible among the subpopulation of patients with diabetic eye disease, who historically have high health care utilization and poor compliance with medication demands. Thus, finding the best schedule for using the most appropriate agent for treating DME may take some trial and error. CASE PRESENTATION This case involves a 71-year-old woman with a 30-year history of type 2 diabetes mellitus. The A1C level at initial evaluation was 8.0%. There is a history of arthritis. Upon presentation, she complained of decreased vision in the left eye. Visual acuity measured 20/25 in the right eye and 20/40 in the left eye. An optical coherence tomography (OCT) scan showed thickening cystic changes in the right and left eye, each involving the macula (Figure 1). The first-line treatment for foveal or center-involved DME is an anti- VEGF injection in this case, bevacizumab was used. Additionally, a patient such as this should be advised to monitor his or her metabolic numbers, as the A1C level is borderline high. Systemic control with respect to blood pressure and blood sugar are important, and patients like this should be asked whether they recently started any new medications: oral glitazones, such as Actose or Avandia, can lead to systemic edema and exacerbation of DME. Because of ongoing edema and poor visual acuity after the initial treatment, the patient was followed on monthly ranibizumab injections in both eyes. After 1 year, visual acuity was 20/40 and therapy fundamentally altered the underlying retinopathy (or at least macular edema) over time, thereby decreasing the need for injections. The former suggests a treatment effect of anti-vegf therapy on the DR, but also hints at the potential to use less-than-monthly dosing for maintenance therapy. Another prescient discovery in the management of DME was that deferred initiation of laser therapy may lead to improved visual acuity, as seen in the diverging lines of visual acuity gain in the prompt and deferred laser groups after year 4 (Figure 4). To a lesser extent, Protocol I may also point to the relative ineffectiveness of laser therapy as additive therapy for patients being managed medically, especially as it relates to reducing the need for injections, as there was almost no difference in the number of anti- VEGF injections ultimately required at 5 years in the ranibizumab plus 20/30 in the right and left eye, respectively, with some anatomic response in the left eye and some persistent DME in the right eye. This raises an important question: What constitutes incomplete response to therapy in DME? In my view, there has been some response in the left eye, although incomplete resolution of the edema; in the right eye, a change in medicine may be reasonable (Figure 2). In this case, the patient was maintained on ranibizumab, with the intertreatment interval extended, per a treat-and-extend (TAE) protocol, to 3 months in the right eye, but only 2 months in the left (Figure 3). There was good response of the anatomy, and so a decision was Figure 1. OCT scans showing foveal involvement in each eye. Figure 2. OCT showing probable incomplete response in the left and right eye after use of bevacizumab, the latter of which may constitute a change in therapy approach. 8 SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016

9 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations Figure 3. TAE was extended to 3 months in the right eye, but only 2 months before relapse in the left with use of ranibizumab. Figure 4. Medication change to aflibercept yielded a 4 month intertreatment interval in the right eye, but still only 2 months in the left. made to switch to aflibercept and attempt a 4-month interval in the right eye; because of persistently poor vision and unresolved edema, an in-class change to aflibercept used every 2 months was made for the left eye (Figure 4). The results of the switch are that the patient could be maintained with good visual acuity and resolved edema with a 4-month treatment interval in the right eye, and aflibercept every 2months in the left eye yielded good control of anatomy and visual acuity (Figure 5). DISCUSSION This case illustrates the value of switching agents because of an inability to extend the interval on one agent, and getting a longer interval, at least in one eye, with a different anti-vegf agent. In this case, each eye required a different treatment schema, with the right eye more responsive to therapy. There are several interesting points about this case: The patient exemplified a variation of responses to all three commonly used anti-vegf therapies, which is seen most clearly in the attempts to extend the intertreatment interval. This suggests that there may be differences in the potency and durability of each of these modalities. Further evidence of this is seen in the results of the DRCR.net Protocol T study.1 This case raises questions about how best to implement a TAE regimen. My preference is that if there is a good response to the particular anti-vegf agent, I extend the interval 1 to 2 weeks for the next injection. But what do you do if the patient is doing well on the current regimen but shows an inability to extend out the intervals? How willing the patient is to keep coming to the office may be an important factor in such a case. If a patient cannot extend beyond 4 weeks, I will consider switching anti-vegf agents; however, if the patient is responding with 6 to 10 week intervals, that may be optimal and it may be of little value to switch the anti-vegf agent. A follow-up point to the TAE discussion is how tolerant the treating physician should be of DME recurrences on current therapy. Certainly macular edema is more tolerated in DME than Figure 5. Despite different treatment intervals in the right and left eye, the effects of the medication switch were ultimately effective. leakage following a retinal vein occlusion or age-related macular degeneration. Yet, there is a limit to which recurrence should be tolerated before therapy change is indicated. On the other end of the spectrum, it is probably unwise to extend the treatment interval beyond 12 weeks, even if the anatomy is responding, because of the risk of recurrent leakage with visual sequelae. Based on Protocol I information, we know that the patients may require steady and consistent injections in the first year or year and a half, but then things tend to taper off for many patients. Therefore, extending and stopping therapy may be reasonable for a majority of patients. Although an unknown variable, the level of systemic control in this patient may have contributed to the varying response to therapy. As retina specialists, we have unique leverage to get people to change behavior, to be compliant with medication, to consider eating well, and to get regular exercise if we educate them about the potential to lose vision. Moreover, I believe we have a responsibility as retina specialists to try and activate and change behavior and optimize systemic status. A fundamental lesson from this case is that real-world treatment JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 9

10 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations of patients can be informed by clinical trial data, although variation from tight protocols used in those trials is often necessary. The VIVID and VISTA 2 and the RISE and RIDE 3 studies were designed to establish safety and to assess potential efficacy of aflibercept and ranibizumab, respectively, for DME. In RISE and RIDE, a monthly injection schedule was used, which was useful for demonstrating the boundaries for safety and efficacy, and thereby establishing information for approval by regulatory agencies. However, that kind of continued treatment is unrealistic in the clinic setting. VIVID and VISTA, in which injections were extended out to every 2 months after initial monthly injections, is perhaps closer to clinical reality, but, again, many patients cannot even comply with every-8- week dosing, and nor should patients be exposed to more therapy than is necessary. Protocol T was arguably closer to a real-world treatment scenario. In that head-to-head study of aflibercept, ranibizumab, and bevacizumab using TAE that is closer to what many practicing physicians use in day-to-day settings, there were important differences in response according to entering visual acuity as seen in the separation of the visual acuity curves between the different drugs. The 2-year data are forthcoming and should tell us more about the longer-term follow-up of patients on TAE treatment protocols in real-world settings. Case information courtesy of John W. Kitchens, MD. 1. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med ;372(13): Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11): Brown DM, Nguyen QD, Marcus DM, et al.; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10): prompt or deferred laser groups. Following the Protocol I study, the manufacturer of ranibizumab sponsored the RISE/RIDE2 study to explore the safety and efficacy of ranibizumab for treating center-involving DME in a phase 3 setting. The study results, which ultimately led to the drug gaining FDA approval, showed that patients gained between 10 and 12 letters of visual acuity at 24 and 36 months, with those changes mirroring improvements in central subfield thickness (CFT). A second anti-vegf agent, aflibercept (Eylea, Regeneron) gained FDA approval for use in center-involved DME based on the results of the VIVID/VISTA phase 3 trial program. 3 Similar to RISE/RIDE, patients gained 10 to 12 letters of acuity and robust improvements in CFT; however, the study demonstrated the utility of an every-8-week dosing paradigm following a loading phase (5 monthly injections followed by dosing every 8 weeks), as opposed to the continuous monthly dosing frequency used in RISE/RIDE. Additional analyses of both RISE/RIDE 12 and VIVID/VISTA 13 showed the utility of the respective agents for slowing the progression of the underlying DR or reducing DR severity scores. The results of these latter studies led to label changes for each agent to include an indication to treat DR in the presence of DME. A more recent study from the DRCR.net offers the potential to have Figure 5. Results from Protocol T study. a similar impact on patient management as did the Protocol I study. The Protocol T study compared bevacizumab, ranibizumab, and aflibercept in a head-to-head fashion following an as-needed, or p.r.n, dosing scheme. 14 (Although not FDA-approved for use in patients with DME, bevacizumab has demonstrated an ability to improve visual acuity compared with laser in smaller clinical trials, 15 and the drug is frequently used in an off-label fashion for this purpose.) The investigators noted a statistical difference among the three agents in the overall population that was not clinically relevant due to the fact that the results were driven by differences in how patients with poorer initial acuity responded to treatment. Patients who entered the study with 20/50 or worse vision did better with aflibercept compared with either ranibizumab or bevacizumab (Figure 5); furthermore, CFT response followed a similar pattern: -101 µm reduction in the bevacizumab group, -147 µm reduction in the ranibizumab group, and a -169 µm reduction in the aflibercept group (aflibercept vs bevacizumab P<.001; aflibercept vs ranibizumab P=.036; and ranibizumab vs bevacizumab P.001). CONCLUSIONS ON THERAPY GOALS: DME It is clear that the gold standard therapy for center-involved DME is anti-vegf therapy and most patients will benefit from anti-vegf therapy, especially if treated early. The emergence of sustainedrelease corticosteroid formulations expands treatment options. These agents are typically used in second-line settings; however, there is growing evidence that DME may be a multimodal disease state, and that certain patients may respond more robustly to corticosteroid therapy as opposed to anti-vegf therapy. The role of combination therapy and questions about when to switch classes (and whom to switch) remain unresolved. Laser therapy, although generally not used for patients with center-involved DME, remains viable for treatment of focal DME as well as noncenter-involved DME. Lastly, although infrequently used in modern treatment of DME, vitrectomy remains a valuable and important option for removing an epiretinal membrane (ERM) or resolving traction secondary to DR. PROLIFERATIVE DIABETIC RETINOPATHY Proliferative DR (PDR) is the end stage of diabetic eye disease and patients who reach this stage are more that likely to lose a substantial amount of vision, which underscores the importance of early recognition and referral. PDR is associated with a number of complications, including vitreous hemorrhage, scar tissue formation (that can lead to traction retinal detachment), and, in the very advanced stage, 10 SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016

11 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations DME is a Multifactorial Disease Sometimes Requiring Multiple Therapeutic Approaches By Jay S. Duker, MD Diabetic macular edema (DME) follows alterations of the blood-retinal barrier that result in increased permeability and leakage. An underlying ischemic and proinflammatory state causes the body to release a host of biochemical factors, principle among them being VEGF, which drives vascular permeability and new blood vessel formation. There is an inflammatory component of DME as well, and it is unclear in most scenarios Figure 1. Fluoroscein angiogram demonsrating nonperfusion in the nasal region. Figure 2. Intravitreal bevacizumab and grid laser was performed on and repeated 2 months later. Figure 3. Edema worsened despite continual monthly therapy with bevacizumab. Figure 4. Intravitreal triamcinolone was attempted, but did not completely resolve the edema. therapy was continued with bevacizumab every 4 to 6 weeks, which yielded a slight reduction in the thickening temporal to fixation, but the central foveal thickness remained abnormal. Bevacizumab therapy was continued for 9 additional months; however, the edema worsened (increased thickening, accumulation of subretinal fluid), and visual acuity dropped to 20/40 (Figure 3). At this point, therapy was switched to intravitreal triamcinolone. At a follow-up visit 1-month after that, the anatomy responded, but some thickening remained, and an evolving PVD was present with visual acuity of 20/50 (Figure 4). At this time, the patient was referred for cataract surgery. Following cataract surgery, bevacizumab was given intravitreally. After a period of continued edema, an in-class change was made to whether the pathophysiology is VEGF-mediated, driven by inflammatory mediators, or a combination of the two. CASE PRESENTATION This case is a 63-year-old man with a 21-year history of type 2 diabetes. The patient s A1C level was 8.8% at the time of initial evaluation and there was past treatment history with panretinal photocoagulation in both eyes and a vitrectomy in the right eye. The patient complained of mild blurring of vision in the right eye, although visual acuity is 20/20. A fluorescein angiogram showed nonperfusion in the nasal retina, as well as neovascularization of the disc, areas of focal leakage in the temporal aspect of the macula, and nonperfusion temporally (Figure 1). An intravitreal injection of bevacizumab was given and grid laser was performed, both of which were repeated 2 months later (Figure 2). Three weeks after the second round of treatment, Figure 5. A switch to ranibizumab also did not yield a complete treatment effect. JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 11

12 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations A B Figure 6. An additional laser treatment finally resolved residual edema. ranibizumab, which did not resolve the edema (Figure 5). Intravitreal triamcinolone was again used in this eye, and 2 months later, there was still macular edema, perhaps slightly better with good visual acuity. At this time, grid laser was added and finally, after that second laser and this intensive treatment, the macular edema had resolved with excellent anatomic and visual outcome (Figure 6). DISCUSSION The complexity of this case is, unfortunately, not an unusual scenario for treating DME, as the case highlights the multifactorial nature of the disease. DME has clear inflammatory and ischemic elements, thus sometimes necessitating multiple modalities to treat it. However, what constitutes anti-vegf nonresponse or failure is not well-defined, nor is it clear when another class of agents or different treatment approach should be initiated. Pseudophakic lens status may provide rationale for earlier initiation of corticosteroids, especially if elevated IOP is not a concern. Such patients may even be considered for corticosteroids as a first-line therapy. The recent market availability of sustained-release corticosteroid implants provides a new mechanism to employ corticosteroids in therapy, particularly in scenarios where the patient may be unwilling or unable to attend regular clinic appointments. Alternately, laser therapy can be added for patients who are not responding well anatomically to anti-vegf injections or corticosteroids. I would especially consider laser for patients who have areas of microaneurysms that are leaking outside of the foveal center. Case information courtesy of John W. Kitchens, MD. neovascular glaucoma all of which result from retinal ischemia which leads to the release of inflammatory and VEGF mediators. Treatment options for PDR include panretinal photocoagulation to ablate peripheral and/or ischemic retina, thereby reducing the amount of VEGF and other mediators released. Anti-VEGF therapy can also result in improvement of retinopathy and regression of neovascularization. The DRCR.net protocol S study 16 suggested Figure 6. Patient with coexisting PDR and DME (A). The patient presented with 20/400 vision, a premacular subhyaloid hemorrhage over the macular area, and areas of extensive ischemia and proliferative disease. The extensive peripheral nonperfusion resulted in ischemia, which led to macular edema and neovascularization (B). Management included a combination of intravitreal anti-vegf therapy and panretinal photocoagulation, which yielded 20/40 vision that was successfully maintained with continual anti-vegf injections. that anti-vegf therapy may be as or more effective than PRP laser therapy for proliferative retinopathy. Severe or nonclearing vitreous hemorrhage and progressive traction retinal detachment can be an indication for vitrectomy surgery. Anti-VEGF therapy can be a valuable adjuvant pre- and postoperatively in many of these cases. Although PDR and DME can present as individual condition, they are often both present in the advanced stages of diabetic eye disease (Figure 6). Such cases often require complicated treatment regimens, with anti-vegf therapy playing a crucial role to both resolve the edema as well as blunt new vessel formation. CONCLUSION: PDR PDR is the leading cause of blindness or complete vision loss in diabetic patients. It is preventable with good glucose and blood pressure control as well as early and aggressive treatment. VEGF plays a role in both PDR and DME pathophysiology, and, thus, use of intravitreal anti- VEGF injections is an important evidence-based and on-label treatment strategy when patients present with both conditions. n 1. Fong DS, Aiello L, Gardner TW, et al.; American Diabetes Association. Retinopathy in diabetes. Diabetes Care. 2004;27 Suppl 1:S Brown DM, Nguyen QD, Marcus DM, et al.; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10): Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11): Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329: Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Early treatment diabetic retinopathy study research group. Arch Ophthalmol. 1985;103(12): Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109(5): Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10): Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10): Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6): e Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2): Ip MS, Domalpally A, Hopkins JJ, et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012;130(9): Michael IP. Abstracts PA053 and PA054. Presented at: AAO Annual Meeting; Nov , 2012; Chicago. 14. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med ;372(13): Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8): Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized trial. JAMA. 2015; 314(20): SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016

13 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations The Rationale for Empowering Patients in Diabetes Self-Management: A Primary Care Provider s Perspective The growing diabetes disease burden in the face of shrinking health care resources suggests a need for a new path forward to improve patient care. By John E. Anderson, MD Over the past 3 decades, the number of Americans diagnosed with diabetes has risen from 5.6 million in 1980 to more than 21 million in 2014 and the Centers for Disease Control and Prevention estimates that an additional 8 million undiagnosed cases may exist. 1 The increase in disease incidence is a true national public health issue, as diabetes is associated with many well-known complications, such as heart disease, stroke, and various organ and macro- and microvascular complications. 1 One complication of diabetes, diabetic retinopathy (DR), is the leading cause of new cases of legal blindness among working-age Americans, affecting about 28.5% of individuals aged older than 40 years, or about 4.2 million individuals. 2 As much as 4.4% of the population, or about 700,000 people, have vision-threatening DR. 2 As many as 6 million individuals may have DR by 2020, with a doubling of those affected by vision-threating DR to about 1.34 million. 2 Rates are difficult to verify in developing nations, but as many as 93 million individuals worldwide, or about 34.6% of the global population, may suffer from DR. 3 The rising diabetes disease burden suggests a need for comprehensive strategies to direct care and manage the many complications of this disease. Within this context, greater advocacy and utilization of diabetes self-management education (DSME) may play a critical role. As defined by an expert panel convened by the American Association of Diabetes Educators (AADE) and the American Diabetes Association (ADA), 4 DSME is the The ongoing process of facilitating the knowledge, skill, and ability necessary for prediabetes and diabetes self-care. This process incorporates the needs, goals, and life experiences of the person with diabetes or prediabetes and is guided by evidence-based standards. The overall objectives of DSME are to support informed decision making, self-care behaviors, problem solving, and active collaboration with the health care team and to improve clinical outcomes, health status, and quality of life. DSME empowers patients in the facilitation of their own care. It incorporates many aspects and standards of care, yet, fundamentally, the existence of DSME acknowledges that patients play a crucial role in daily disease management to avoid the onset of complications. 5-9 Additionally, the DSME framework is intended to build teamwork and collaboration among the many health care providers patients with diabetes interact with, especially in creating opportunities for those care providers to act as facilitators of self-guided care. As such, on a very basic level, asking patients at each and every encounter about his or her A1C levels serves as a safeguard against uncontrolled disease as well as a reminder of the patient s responsibility to continually monitor the disease. Figure 1. Age-adjusted percentage of US adults 18 years or older with diagnosed diabetes receiving a dilated eye exam in the last year. RISK FACTORS FOR DR Development of DR and other microvascular complications are closely associated with duration of hyperglycemia among individuals with type 1 diabetes. Although body mass and coexisting hypertension are additive risk factors, the duration of systemic diabetes, especially if it is uncontrolled, is the strongest risk factor influencing DR development. Among individuals with type 1 diabetes, about a quarter will develop some degree of retinopathy within 5 years, about 60% by 10 years, and around 80% by 15 years. 10,11 Among individuals older than 30 with type 2 diabetes not requiring insulin with less than 5 years duration of diabetes, about 24% have some form of DR; 40% of patients with insulin-dependent type 2 diabetes develop DR. 10 At 19 years duration, 53% of the non-insulin using and 84% of the insulin-using individuals with type 2 diabetes develop DR. 10 About 2% of individuals will develop proliferative DR within 5 years of disease onset, and about 25% within 25 years. 10 These numbers have led some to question insulin use as a trigger for the development of DR. Yet, this may be more a matter of selection bias, as those patients requiring insulin likely have more severe disease, the extent of which is more likely to be the primary contributor to vascular complications such as DR. LOST OPPORTUNITIES FOR DISEASE RECOGNITION Recommendations from the American Diabetes Association JANUARY/FEBRUARY 2016 SUPPLEMENT TO RETINA TODAY 13

14 Evolving Issues in Diabetic Vascular Complications: Understanding Ocular Manifestations Figure 2. Percentage of patients with diabetes receiving annual dilated fundus examination, by age. suggest that patients older than 10 years with known diabetes receive a retinal screening, performed by an ophthalmologist or an optometrist, within 5 years of the diagnosis of type 1 diabetes; for individuals with type 2 diabetes, a screening is recommended shortly after the diagnosis is made. 12 Follow-up examinations should occur annually if the retinopathy is not progressing, and with greater frequency if the disease is advancing. Women with diabetes contemplating pregnancy should be screened before they get pregnant and again during pregnancy. Although these guidelines represent the presumed standard of care, in reality, screening for diabetic eye disease is much lower than optimal (Figure 1). 13 The data indicate that there is tremendous lost opportunity: 37% of patients who require screening do not get it, and the trends suggest that the situation has not changed much over time. There appears to be a slightly better screening rate among older individuals, yet still well below optimal levels (Figure 2) and it may be necessary to state the obvious, that earlier screening may help save vision. Diabetes is a disease that does not discriminate by racial group, although data suggest higher incidence among Hispanics and blacks. 11 Yet, screening rates are similar among all ethnicities (Figure 3). It is hoped that as access to care improves, that these numbers will begin to display an upward trend. It appears that higher education level, better insurance, and greater access correlate with increased rates of screening. 6 A POTENTIAL SOLUTION Primary care providers caring for individuals with diabetes have many priorities, including but not limited to measuring glycemic control, checking blood pressure, foot and possible dental examinations, and assessing urinary albumin excretion, renal function, and medical adherence. Add to this whatever other medical needs the patient may present with, and there is precious little time to perform a dilated fundus examination. A possible solution, then, is greater utilization of DSME, which is an essential component of newly diagnosed patients understanding their disease and the ramifications of letting the systemic control lapse. Yet, emphasis on DSME cannot be a one-time commitment: Patients who struggle with their disease or who cannot reach their A1C goal needs to be reminded and possibly referred back for further education. On a very basic level, it simply is not adequate to ask about hemoglobin A1C level; patients need to understand why this is an important factor in reducing the risk of microvascular disease. Another example is the relative danger Figure 3. Percentage of patients with diabetes receiving annual dilated fundus examination, by race/ethnicity. of asymptomatic DR because if patients wait for symptoms to occur before visiting an eye doctor, in diabetes, it is often too late. CONCLUSION Primary care providers are simply becoming overwhelmed by the shifting landscape of health care. More patients require services, many of which are getting delegated to nurse practitioners and physician assistants. Yet the need to properly educate patients with diabetes about microvascular complications is omnipresent and growing more important with the rising disease incidence. Whatever the long-term solution may be, it is crucial in the immediate term to start to emphasize the importance of glycemic control, particularly in the early stage of the disease. Patients must be educated about the importance of screening for DR, the implications of microvascular disease, and about the danger of asymptomatic DR. On the primary care side, physicians need to have questions about the dilated retinal examination incorporated into regular clinical encounters with patients known to have diabetes. Our colleagues in the eye care field can greatly facilitate this effort through open collaboration and improved communication so that together we can build health care teams dedicated to helping patients with diabetes understand and help manage their own care. n 1. US Centers for Disease Control and Prevention. National Diabetes Surveillance System. Age-adjusted prevalence of obesity and diagnosed diabetes among US adults Klein, BE. Overview of epidemiologic studies of diabetic retinopathy among US adults. Opthalmic Epidemiology. 2007;14(4): Yau JW, Rogers SL, Kawasaki R, et al; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3): Haas L, Maryniuk M, Beck J, et al; 2012 Standards Revision Task Force. National standards for diabetes self-management education and support. Diabetes Care. 2014;37 Suppl 1:S144-S Brown SA. Interventions to promote diabetes self-management: state of the science. Diabetes Educ. 1999;25(Suppl.): Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults with type 2 diabetes: a metaanalysis of the effect on glycemic control. Diabetes Care 2002;25: Gary TL, Genkinger JM, Guallar E, Peyrot M, Brancati FL. Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes. Diabetes Educ. 2003;29: Deakin T, McShane CE, Cade JE, Williams RD. Group based training for self-management strategies in people with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(2):CD Renders CM, Valk GD, Griffin SJ, et al. Interventions to improve the management of diabetes in primary care, outpatient, and community settings: a systematic review. Diabetes Care. 2001;24: Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102(4): Varma R, Torres M, Peña F, et al; Los Angeles Latino Eye Study Group. Prevalence of diabetic retinopathy in adult Latinos: the Los Angeles Latino eye study. Ophthalmology. 2004;111(7): Standards of Medical Care in Diabetes Diabetes Care. 2015;389(Suppl 1):S1-S Behavioral Risk Surveillance System. CDC Division of Diabetes Translation. Accessed January 18, SUPPLEMENT TO RETINA TODAY JANUARY/FEBRUARY 2016